2-Aminobenzimidazoles as potent ITK antagonists: trans-stilbene-like moieties targeting the kinase specificity pocket.
Based on the information from molecular modeling and X-ray crystal structures, the kinase specificity pocket of ITK could be occupied upon extension of the right-hand-side of the 2-benzimidazole core of the inhibitors. 2-Aminobenzimidazoles with a trans-stilbene-like extension were designed and synthesized as novel ITK antagonists. Significant improvement on binding affinity and cellular activity were obtained through the trans-stilbene-like antagonists. Several compounds showed inhibitory activity in an IL-2 functional assay.
Lo
Ho Yin
HY
Medicinal Chemistry, Boehringer Ingelheim Pharmaceuticals Inc., 900 Ridgebury Road, P.O. Box 368, Ridgefield, CT 06877, USA. ho-yin.lo@boehringer-ingelheim.com
Bentzien
Jörg
J
Fleck
Roman W
RW
Pullen
Steven S
SS
Khine
Hnin Hnin
HH
Woska
Joseph R
JR
Kugler
Stanley Z
SZ
Kashem
Mohammed A
MA
Takahashi
Hidenori
H
D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D020650:Combinatorial Chemistry Techniques; D018360:Crystallography, X-Ray; D015195:Drug Design; D015394:Molecular Structure; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism; D013267:Stilbenes / Q000737:chemistry*; D013329:Structure-Activity Relationship
D001562:Benzimidazoles; D013267:Stilbenes; C027391:2-aminobenzimidazole; C089848:Tec protein-tyrosine kinase; D011505:Protein-Tyrosine Kinases